Pteridinone derivatives as modulators of chemokine receptor activity

ABSTRACT

The invention provides certain pteridinone compounds of formula (I), processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.

The present invention relates to certain heterocyclic compounds,processes and intermediates used in their preparation, pharmaceuticalcompositions containing them and their use in therapy.

Chemokines play an important role in immune and inflammatory responsesin various diseases and disorders, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis. These small secreted molecules are a growingsuperfamily of 8-14 kDa proteins characterised by a conserved fourcysteine motif. At the present time, the chemokine superfamily comprisesthree groups exhibiting characteristic structural motifs, the Cys-X-Cys(C—X—C), Cys-Cys (C—C)) and Cys-X₃-Cys (C X₃—C) families. The C—X—C andC—C families have sequence similarity and are distinguished from oneanother on the basis of a single amino acid insertion between theNH-proximal pair of cysteine residues. The C—X₃—C family isdistinguished from the other two families on the basis of having atriple amino acid insertion between the NH-proximal pair of cysteineresidues.

The C—X—C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL8) andneutrophil-activating peptide 2 (NAP-2).

The C—C chemokines include potent chemoattractants of monocytes andlymphocytes but not neutrophils. Examples include human monocytechemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated onActivation, Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

The C—X₃—C chemokine (also known as fractalkine) is a potentchemoattractant and activator of microglia in the central nervous system(CNS) as well as of monocytes, T cells, NK cells and mast cells.

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1,CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX₃CR1 for theC—X₃—C family. These receptors represent good targets for drugdevelopment since agents which modulate these receptors would be usefulin the treatment of disorders and diseases such as those mentionedabove.

The present invention therefore provides compounds of formula (I) andpharmaceutically acceptable salts, solvates or in vivo hydrolysableesters thereof:

in which:

-   -   R¹ represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or        C₂-C₆ alkynyl group, each of which may be optionally substituted        by one or more substituent groups independently selected from        halogen atoms, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,        —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, an aryl or heteroaryl group,        which last two may themselves be optionally substituted by one        or more substituents independently selected from halogen atoms,        cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,        —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl or trifluoromethyl groups;    -   R² and R³ each independently represent a hydrogen atom, or a        C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl        group, the latter four groups may be optionally substituted by        one or more substituent groups independently selected from:    -   (a) halogen atoms, —OR⁴, —NR⁵R⁶—CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,        —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹;    -   (b) a 3-8 membered ring optionally containing one or more atoms        selected from O, S, NR⁸ and itself optionally substituted by        C₁-C₃ alkyl or halogen; or    -   (c) an aryl group or heteroaryl group each of which may be        optionally substituted by one or more substituents independently        selected from halogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶,        —CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl and        trifluoromethyl groups;    -   R⁴ represents hydrogen or a C₁-C₆ alkyl group which may be        optionally substituted by one or more substituent groups        independently selected from halogen atoms, —OR¹¹, —NR⁵R⁶, or an        aryl group or heteroaryl group either of which may be optionally        substituted by one or more substituents independently selected        from halogen atoms, cyano, nitro, —OR¹¹, —NR⁵R⁶, —CONR⁵R⁶,        —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂, C₁-C₆ alkyl and trifluoromethyl        groups; or    -   R⁴ represents a halogen atom, —OR¹¹, —NR⁵R⁶, or an aryl group or        heteroaryl group either of which may be optionally substituted        by one or more substituents independently selected from halogen        atoms, cyano, nitro, —OR¹¹, —NR⁵R⁶, —CONR⁵R⁶, —NR⁸COR⁹,        —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl and trifluoromethyl groups;    -   R⁵ and R⁶ independently represent a hydrogen atom or a C₁-C₆        alkyl or phenyl group or heteroaryl group the latter three of        which may be optionally substituted by one or more substituent        groups independently selected from halogen atoms, phenyl, —OR¹⁴        and —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶        or    -   R⁵ and R⁶ together with the nitrogen atom to which they are        attached form a 4 to 7-membered saturated heterocyclic ring        system optionally containing a further heteroatom selected from        oxygen and nitrogen atoms, which ring system may be optionally        substituted by one or more substituent groups independently        selected from phenyl, —OR¹⁴, —COOR¹⁴, NR¹⁵R¹⁶, —CONR¹⁵R¹⁶,        —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁-C₆ alkyl, itself        optionally substituted by one or more substituents independently        selected from halogen atoms and —NR¹⁵R¹⁶ and —OR¹⁷ groups;    -   R¹⁰ represents a C₁-C₆-alkyl or a phenyl group, either of which        may be optionally substituted by one or more substituent groups        independently selected from halogen atoms, phenyl, —OR¹⁷ and        —NR¹⁵R¹⁶,    -   Y represents NR²⁰R²¹, OR⁴, SR⁴, a heteroaryl group or NR⁵R⁶        where R⁵ and R⁶ together with the nitrogen atom to which they        are attached form a 4 to 7-membered saturated heterocyclic ring        system optionally containing a further heteroatom selected from        oxygen and nitrogen atoms, which ring system may be optionally        substituted by one or more substituent groups independently        selected from phenyl, —OR¹⁴, —COOR¹⁴, —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶,        —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁-C₆ alkyl, itself        optionally substituted by one or more substituents independently        selected from halogen atoms and —NR¹⁵R¹⁶ and —OR¹⁷ groups;    -   each of R⁷, R⁸, R⁹, R¹¹, R¹⁴ R¹⁵, R¹⁶ and R¹⁷ independently        represents a hydrogen atom or a C₁-C₆, alkyl, or a phenyl group;    -   and R²⁰ and R²¹ are defined as for R² and R³

The present invention further provides compounds of formula (I) andpharmaceutically acceptable salts or solvates thereof:

in which:

-   -   R represents a C₃-C₇carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or        C₂-C₆ alkynyl group, each of which may be optionally substituted        by one or more substituent groups independently selected from        halogen atoms, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸ COR⁹, —SR¹⁰,        —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, an aryl or heteroaryl group,        which last two may themselves be optionally substituted by one        or more substituents independently selected from halogen atoms,        cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,        —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl or trifluoromethyl        groups;    -   R² and R³ each independently represent a hydrogen atom, or a        C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl        group, the latter four groups may be optionally substituted by        one or more substituent groups independently selected from:    -   (a) halogen atoms, —OR⁴, —NR⁵R⁶—CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,        —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹;    -   (b) a 3-8 membered ring optionally containing one or more atoms        selected from O, S, NR⁸ and itself optionally substituted by        C₁-C₃-alkyl or halogen; or    -   (c) an aryl group or heteroaryl group each of which may be        optionally substituted by one or more substituents independently        selected from halogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶,        —CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl and        trifluoromethyl groups;    -   R⁴ represents hydrogen or a C₁-C₆ alkyl group the latter of        which may be optionally substituted by one or more substituent        groups independently selected from halogen atoms, —OR¹¹, —NR⁵R⁶,        or an aryl group or heteroaryl group either of which may be        optionally substituted by one or more substituents independently        selected from halogen atoms, cyano, nitro, —OR¹¹, —NR⁵R⁶,        —CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl and        trifluoromethyl groups;    -   R⁵ and R⁶ independently represent a hydrogen atom or a C₁-C₆        alkyl or phenyl group the latter two of which may be optionally        substituted by one or more substituent groups independently        selected from halogen atoms, phenyl, —OR¹⁴ and —NR¹⁵R¹⁶,        —CONR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶        or    -   R⁵ and R⁶ together with the nitrogen atom to which they are        attached form a 4- to 7-membered saturated heterocyclic ring        system optionally containing a further heteroatom selected from        oxygen and nitrogen atoms, which ring system may be optionally        substituted by one or more substituent groups independently        selected from phenyl, —OR¹⁴, —COOR¹⁴, —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶,        NR¹⁵COR¹⁶, SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁-C₆ alkyl, itself        optionally substituted by one or more substituents independently        selected from halogen atoms and —NR¹⁵R¹⁶ and —OR¹⁷ groups;    -   R¹⁰ represents a C₁-C₆-alkyl or a phenyl group, either of which        may be optionally substituted by one or more substituent groups        independently selected from halogen atoms, phenyl, —OR¹⁷ and        —NR¹⁵R¹⁶,    -   Y is NR²⁰R²¹, OR⁴ or SR⁴;    -   each of R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴ R¹⁵, R¹⁶ , R¹⁷, R¹⁸ and        R¹⁹ independently represents a hydrogen atom or a C₁-C₆, alkyl,        or a phenyl group;    -   and R²⁰ and R²¹ are defined as for R² and R³.

In the context of the present specification, unless otherwise indicated,the term alkyl includes both straight-chain and branched-chain alkylgroups. However references to individual alkyl groups such as “propyl”are specific for the straight chain version only and references toindividual branched-chain alkyl groups such as t-butyl are specific forthe branched chain version only. Examples of C₁-C₃ alkyl include methyl,ethyl, propyl. Examples of C₁-C₆ alkyl include the examples of C₁-C₃alkyl and additionally butyl, t-butyl, pentyl, 2methylbutyl and hexyl.Examples of C₁-C₈ alkyl include the examples of C₁-C₆alkyl andadditionally heptyl, 2-ethyl-3-methylbutyl and octyl. An analogousconvention applies to other terms such as alkenyl and alkynyl. Forexample C₂-C₆ alkenyl includes vinyl, allyl, 1-propenyl, 2-butenyl,2methylbut-2-enyl, and 4-hexenyl. Examples of C₂-C₆ alkynyl includeethynyl, 1-propynyl, 2-propynyl and 1-methylpent-2ynyl.

C₃-C₇ carbocyclic is a saturated, partially saturated or unsaturatedring system containing 3 to 7 ring carbon atoms. C₃-C₇ carbocyclicgroups include cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl.

Examples of 4 to 7-membered saturated heterocyclic ring systemsoptionally containing a further heteroatom selected from oxygen andnitrogen atoms include azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl and piperazinyl.

Aryl groups include phenyl and naphthyl. Heteroaryl is defined as a 5-or 6membered aromatic ring containing one or more heteroatoms selectedfrom N, S, O. Examples include pyridine, pyrimidine, thiazole, oxazole,pyrazole, imidazole, furan.

Further examples include pyridine, pyrimidine, thiazole, oxazole,pyrazole, imidazole, furan, triazole and thiadiazole.

Halogen atoms include fluorine, chlorine, bromine and iodine. Preferredhalogen atoms are fluorine and chlorine.

Where a group is substituted or optionally substituted by one or moresubstitutents it is to be understood that this definition includes allsubstituents being chosen from one of the specified groups or thesubstituents being chosen from two or more of the specified groups.Preferably one or more means 1, 2 or 3. One or more may also mean 1 or2. Where a ring contains or optionally contains one or more atoms,preferably it contains 1, 2, 3 or 4 atoms.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

The invention further encompasses all solvated forms of compounds offormula (I) and salts thereof.

Preferred values of R¹, R², R³ and Y are as follows. Such values may beused where appropriate with any of the definitions, claims orembodiments defined hereinbefore or hereinafter.

Suitably the group R¹ represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆alkenyl or C₂-C₆ alkynyl group, each of which may be optionallysubstituted by one or more substituent groups independently selectedfrom halogen atoms, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,—SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, an aryl or heteroaryl group both of whichcan be optionally substituted by one or more substituents independentlyselected from halogen atoms, cyano, nitro, —OR⁴, NR⁵R⁶, —CONR⁵R⁶,—COOR⁷, —NR⁸COR¹⁰, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R¹⁰, C₁-C₆ alkyl ortrifluoromethyl groups. Particularly advantageous compounds of formula(I) are those in which R¹represents an optionally substituted benzylgroup. More preferably R¹ represents benzyl or benzyl substituted by oneor more C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen atoms, in particularbenzyl substituted by two halogen atoms.

Preferably one of R² and R³ is hydrogen and the other is C₁-C₈ alkylsubstituted by hydroxy and one or more methyl or ethyl groups. Morepreferably one of R² and R³ is hydrogen and the other is CH(CH₃)CH₂OH,CH(Et)CH₂OH, C(CH₃)₂CH₂OH or CH(CH₂OH)₂. When one of R² and R³ ishydrogen and the other is CH(CH₃)CH₂OH or CH(Et)CH₂OH the resultingcompounds of formula (I) are preferably in the form of the (R) isomer.Most preferably one of R² and R³ is hydrogen and the other isCH(CH₃)CH₂OH.

Preferably Y represents —NR²⁰R²¹, —OR⁴, SR⁴, a heteroaryl group or—NR⁵R⁶ where R⁵ and R⁶ together with the nitrogen atom to which they areattached form a 4 to 7-membered saturated heterocyclic ring systemoptionally containing a further heteroatom selected from oxygen andnitrogen atoms, which ring system may be optionally substituted by oneor more substituent groups independently selected from —OH, —NH₂ orC₁-C₄ allyl.

Preferably one of R²⁰ and R²¹ is hydrogen or methyl and the other is aC₃-C₇carbocyclic substituted by hydroxy or it is C₁-C₄alkyl substitutedby —OR⁴, heteroaryl optionally substituted by methyl, or a 3-8 memberedring optionally containing one or more atoms selected from O, S and NR⁸.

Preferably R⁴ represents hydrogen or a C₁-C₆ alkyl group the latter ofwhich may be optionally substituted by —NR⁵R⁶ or an heteroaryl groupwhich may be optionally substituted by one or more substituentsindependently selected from halogen atoms, cyano, nitro, —OR¹¹, —NR⁵R⁶₃, —CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl andtrifluoromethyl groups; or

-   -   R⁴ represents a heteroaryl group which may be optionally        substituted by one or more substituents independently selected        from —OH and methyl.

Preferably one of R⁵ and R⁶ is hydrogen and the other is C₁-C₆alkyl or aheteroaryl group; or together with the nitrogen atom to which they areattached R⁵ and R⁶ form a 4- to 7-membered saturated heterocyclic ringsystem optionally containing a further heteroatom selected from oxygenand nitrogen atoms, which ring system may be optionally substituted byone or more substituent groups independently selected from —OH, —NH₂ orC₁-C₄ alkyl.

A preferred class of compound is of formula (I) in which;

-   -   R¹ represents benzyl or benzyl substituted by one or more C₁-C₆        alkyl, C₁-C₆ alkoxy, or halogen atoms;    -   R² represents hydrogen;    -   R³ represents C₁-C₈ alkyl substituted by hydroxy and one or more        methyl or ethyl groups;    -   Y represents —NR²⁰R²¹, —OR⁴, —SR⁴, a heteroaryl group or —NR⁵R⁶;    -   R²⁰ represents hydrogen or methyl;    -   R²¹ represents a C₃-C₇carbocyclic substituted by hydroxy; or        C₁-C₄alkyl substituted by —OR⁴, heteroaryl (optionally        substituted by methyl), or a 3-8 membered ring optionally        containing one or more atoms selected from O, S and NR⁸;    -   R⁴ represents hydrogen or a C₁-C₆ alkyl group optionally        substituted by —NR⁵R⁶ or an heteroaryl group optionally        substituted by one or more substituents independently selected        from halogen atoms, cyano, nitro, —OR¹¹, —NR⁵R⁶, —CONR⁵R⁶,        —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl and trifluoromethyl        groups; or R⁴represents a heteroaryl group optionally        substituted by one or more substituents independently selected        from —OH and methyl;    -   R⁵ represents hydrogen;    -   R⁶ represents C₁-C₆alkyl or a heteroaryl group;    -   or R⁵ and R⁶ together with the nitrogen atom to which they are        attached form a 4 to 7-membered saturated heterocyclic ring        system optionally containing a further heteroatom selected from        oxygen and nitrogen atoms, which ring system may be optionally        substituted by one or more substituent groups independently        selected from —OH, —NH₂ or C₁-C₄ alkyl;    -   R⁸ represents a hydrogen atom or a C₁-C₆ alkyl or a phenyl        group;    -   R⁹ represents a hydrogen atom or a C₁-C₆ alkyl or a phenyl        group; and    -   R¹¹ represents a hydrogen atom or a C₁-C₆ alkyl or a phenyl        group.

Another preferred class of compound is of formula (I) in which;

-   -   R¹ represents benzyl substituted by two halogen atoms;    -   R² represents hydrogen;    -   R³ represents CH(CH₃)CH₂OH, CH(Et)CH₂OH, C(CH₃)₂CH₂OH or        CH(CH₂OH)₂;    -   Y represents —NR²⁰R²¹, —OR⁴, —SR⁴, a heteroaryl group or —NR⁵R⁶;    -   R²⁰ represents hydrogen or methyl;    -   R²¹ represents a C₃-C₇carbocyclic substituted by hydroxy; or        C₁-C₄alkyl substituted by —OR⁴, heteroaryl (optionally        substituted by methyl), or a 3-8 membered ring optionally        containing one or more atoms selected from O, S and NR⁸;    -   R⁴ represents hydrogen or a C₁-C₆ alkyl group optionally        substituted by —NR⁵R⁶ or an heteroaryl group optionally        substituted by one or more substituents independently selected        from halogen atoms, Cyano, nitro, —OR¹¹, —NR⁵R⁶, —CONR⁵R⁶,        —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl and trifluoromethyl        groups; or R⁴ represents a heteroaryl group optionally        substituted by one or more substituents independently selected        from —OH and methyl;    -   R⁵ represents hydrogen;    -   R⁶ represents C₁-C₆alkyl or a heteroaryl group;    -   or R⁵ and R⁶ together with the nitrogen atom to which they are        attached form a 4- to 7-membered saturated heterocyclic ring        system optionally containing a further heteroatom selected from        oxygen and nitrogen atoms, which ring system may be optionally        substituted by one or more substituent groups independently        selected from —OH, —NH₂ or C₁-C₄ alkyl;    -   R⁸ represents a hydrogen atom or a C₁-C₆ alkyl or a phenyl        group;    -   R⁹ represents a hydrogen atom or a C₁-C₆ alkyl or a phenyl        group; and    -   R¹¹ represents a hydrogen atom or a C₁-C₆ alkyl or a phenyl        group.

Another preferred class of compound is of formula (I) in which;

-   -   R¹ represents benzyl substituted by two fluorine atoms;    -   R² represents hydrogen;    -   R³ represents CH(CH₃)CH₂OH;    -   Y represents (2-hydroxyethyl)amino, (phenylmethyl)amino, amino,        1H-imidazolyl, (1-methyl-1-imidazolyl)thio, methoxy,        (3-pyridylmethyl)amino, [(5-methyl-2-furanyl)methyl]amino,        3,5-dimethyl-1-piperazinyl,        N-methyl-N-[(3-methyl-5-isoxazolyl)methyl]amino,        [2-(2-pyrimidinylamino)ethyl]amino, 4morpholinyl,        [2-(4-morpholinyl)ethyl]amino, (2-methoxyethyl)amino,        (2-furanylmethyl)amino, 1-azetidinyl,        [(5-methylpyrazinyl)methyl]amino, [2-(2-furanyl)ethyl]amino,        [3-(4morpholinyl)propyl]amino,        [3-methyl-5-isoxazolyl)methyl]amino, 3-hydroxy-1-pyrrolidinyl,        (2-furanylmethyl)thio, (2-hydroxypropyl)amino,        [2-(dimethylamino)ethyl]thio, (2-hydroxypropyl)amino,        (3-hydroxypropyl)amino, N-(2-hydroxyethyl)-N-methylamino,        (5-hydroxy-4-methyl4H-1,2,4-triazol-3-yl)thio,        (4-hydroxycyclohexyl)amino, 1,3,4-thiazol-2-ylthio,        [4-hydroxy-2-cyclopenten-1-yl]amino, 3-hydroxy-1-pyrrolidinyl,        3-hydroxy-3-methyl-1-azetidinyl, 3-amino-1-pyrrolidinyl and        (2-aminoethyl)thio.

Particularly preferred compounds of the invention include:

-   -   2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-hydroxyethyl)amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)pteridinone;    -   2[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(phenylmethyl)amino]-7(8H)pteridinone;    -   2-[[(2,3-Difluorophenyl)methyl]thio-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6,7-pteridinedione;    -   6-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;    -   2-[[2,3-difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(1H-imidazol-1-yl)-7(8H)pteridinone;    -   2-[[2,3-difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-[(1-methyl-1-imidazol-2-yl)thio]-7(8H)-pteridinone;    -   2-[[2,3-difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]6-methoxy-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3-pyridinylmethyl)amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[(5-methyl-2-furanyl)methyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-6-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino)-6-methyl[(3-methyl-5-isoxazolyl)methyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[2-(2-pyrimidinylamino)ethyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3        difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(4-morpholinyl)7(8H)-pteridinone;    -   2[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[2-(4-morpholinyl)ethyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(2-methoxyethyl)amino]-7(8H)pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-furanylmethyl)amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;    -   6(1-azetidinyl)-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[(5-methylpyrazinyl)methyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-6-[[2-(2-furanyl)ethyl]amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[3-(4-morpholinyl)propyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2hydroxy-1-methylethyl]amino)-6-[[(3-methyl-5-isoxazolyl)methyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3S)-3-hydroxy-1pyrrolidinyl]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-furanylmethyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(2-hydroxypropyl)amino]-7(8H)pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-6-[[2-(dimethylamino)ethyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[(2S)-2-hydroxypropyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3-hydroxypropyl)amino]-7(8H)-pteridinone;    -   2[[(2,3-difluorophenyl)methyl]thio]-6-[(2-hydroxyethyl)methylamino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(5-hydroxy4methyl4H-1,2,4triazol-3-yl)thio]-7(8H)-pteridinone;    -   2-[[(2,3        difluorophenyl)methyl]thio]-6-[(4hydroxycyclohexyl)amino]-4-[[(1R)-2hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(1,3,4-thiadiazol-2-ylthio)-7(8H)-pteridinone;    -   2[[(2,3-difluorophenyl)methyl]thio]-6-[[(1S,4R)-4-hydroxy-2-cyclopenten-1-yl]amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-4-[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-7(8H)-pteridinone;    -   2-[[(2,3-difluorophenyl)methyl]thio]-6-(3-hydroxy-3-methyl-1-azetidinyl)-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)pteridinone;    -   6-[(3S)-3-amino-1-pyrrolidinyl]-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;        and    -   6-[(2-aminoethyl)thio]-2-[[(2,3difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone.

According to the invention there is also provided a process for thepreparation of:—

-   -   (a) a compound of formula (I) where Y is NR²⁰R²¹ which comprises        treatment of a compound of formula (IIA) where R¹, R² and R³ are        as defined in formula (I) or are protected derivatives thereof        and L is a leaving group such as bromo with an amine HNR²⁰R²¹,    -   (b) a compound of formula (I) where Y is OR⁴ which comprises        treatment of a compound of formula (IIA) where R¹, R² and R³ are        as defined in formula (I) or are protected derivatives thereof        and L is a leaving group such as bromo with an alcohol R⁴OH,    -   (c) a compound of formula (I) where Y is SR⁴ which comprises        treatment of a compound of formula (IIA) where R¹, R² and R³ are        as defined in formula (I) or are protected derivatives thereof        and L is a leaving group such as bromo with a thiol R⁴SH,    -   (d) a compound of formula (I) where Y is NR⁵R⁶which comprises        treatment of a compound of formula (IIA) where R¹, R² and R³ are        as defined in formula (I) or are protected derivatives thereof        and L is a leaving group such as bromo with an amine H NR⁵R⁶    -   (e) a compound of formula (I) where Y is a heteroaryl group        which comprises treatment of a compound of formula (IIA) where        R¹, R² and R³ are as defined in formula (I) or are protected        derivatives thereof and L is a leaving group such as bromo with        a heteroarene.    -   (f) a compound of formula (I) where Y is OH which comprises        treatment of a compound of formula (IIB):        where R¹, R² and R³ are as defined in formula (I) or are        protected derivatives thereof with diethyl oxalate, or    -   (g) a compound of formula (I) where Y is NH₂ which comprises        treatment of a compound of formula (IIB) where R¹, R² and R³ are        as defined in formula (I) or are protected derivatives    -   thereof with iminomethoxy-acetic acid, methyl ester        hydrochloride, and optionally thereafter process (a), (b),        (c), (d) or (e) and in any order.        -   removing any protecting groups        -   forming a pharmaceutically acceptable salt, solvate or in            vivo hydrolysable ester.

The reaction of compounds of formula (IIA) with an amine HNR²⁰R²¹ may beperformed in a solvent such as N-methylpyrrolidinone at a temperaturebetween 0° C. and 150° C. in the presence of a base such asN,N-diisopropylethylamine.

The reaction of compounds of formula (IIA) with an alcohol R⁴OH may beperformed using the alcohol R⁴OH as solvent at a temperature between 0°C. and 150° C. in the presence of a base such as butyllithium.

The reaction of compounds of formula (IIA) with a thiol R⁴SH may beperformed in a solvent such as DMSO at a temperature between 0° C. and150° C. in the presence of a base such as potassium tert-butoxide.

The reaction of compounds of formula (IIA) with an amine HNR⁵R⁶ may beperformed in a solvent such as N-methylpyrrolidinone at a temperaturebetween 0° C. and 150° C. in the presence of a base such asN,N-diisopropylethylamine.

The reaction of compounds of formula (IIA) with a heteroarene may beperformed in a solvent such as DMSO at a temperature between 0° C. and100° C. in the presence of a base such as potassium tert-butoxide.

The reaction of compounds of formula (IIB) with diethyl oxalate may beperformed in the absence of solvent at a temperature between 50° C. and200° C.

The reaction of compounds of formula (IIB) with iminomethoxy-aceticacid, methyl ester hydrochloride may be performed in ethanol in thepresence of base such as N,N-diisopropylethylamine at a temperaturebetween 0° C. and 150° C.

Compounds of formula (IIA) where R¹, R² and R³ are as defined in formula(I) and L is bromo may be prepared from compounds of formula (IIA) whereR¹, R² and R³ are as defined above and L is hydrogen by treatment withbromine in a solvent such as acetonitrile at a temperature between 0° C.and 100° C.

Compounds of formula (IIA) where R¹, R² and R³ are as defined in formula(I) and L is hydrogen may be prepared from compounds of formula (III)where R¹ is as defined above and X is a leaving group such as bromo bytreatment with an amine HNR²R³. The reaction may be performed in asolvent such as N-methylpyrrolidinone at a temperature between 0° C. and150° C. in the presence of a base such as N,N diisopropylethylamine.

Compounds of formula (III) where R¹ is as defined in formula (I) and Xis a leaving group such as bromo may be prepared by treating a compoundof formula (III) where R¹ is as defined above and X is NH² with adiazotizing agent such as isoamyl nitrite in the presence of ahalogenating agent such as bromoform. The reaction may be performed in asolvent such as DMSO at a temperature between 0° C. and 150° C.

Compounds of formula (III) where R¹ is as defined in formula (I) and Xis NH₂ may be prepared by treatment of a compound of formula (IV):

where R¹ is as defined above with triethyl phosphonoacetate in thepresence of a base such as butyllithium. The reaction may be carried outin a solvent such as DMF at a temperature between 0° C. and 100° C.

Compounds of formula (IV) where R¹ is as defined in formula (I) may beprepared by treating a compound of formula (V) where R¹ is as definedabove with a nitrosating agent such as sodium nitrite. The reaction maybe performed in a solvent such as aqueous acetic acid at a temperaturebetween 0° C. and 100° C.

Compounds of formula (V) where R¹ is as defined in formula (I) may beprepared by treating a compound of formula (VI) with a compound offormula R¹X where R¹ is as defined above and X is a leaving group suchas bromide in the presence of a base such as potassium tert-butoxide.The reaction may be performed in a solvent such as DMSO at roomtemperature.

Compounds of formula (IIB) where R¹, R² and R³ are as defined in formula(I) may be prepared by treatment of compounds of formula (VII) where R¹,R² and R³ are as defined above with a reducing agent such as zinc. Thereaction may be performed in a solvent such as ethanol at reflux.

Compounds of formula (VII) where R¹, R² and R³ are as defined in formula(I) may be prepared by treatment of compounds of formula (VIII) whereR¹, R² and R³ are as defined above with a nitrosating agent such assodium nitrite in acetic acid. The reaction may be conveniently carriedout at room temperature.

Compounds of formula (VIII) where R¹, R² and R³ are as defined informula (I) may be prepared by treatment of compounds of formula (IX)where R¹ is as defined in formula (I) and L is a leaving group such aschloro with an amine HNR²R³. The reaction can be carried out in asolvent such as N-methylpyrrolidinone at elevated temperature, forexample at between 50° C. and 200° C.

Compounds of formula (IX) where R¹ is as defined in formula (I) and L isa leaving group such as chloro may be prepared by treatment of compoundsof formula (IX) where R¹ is as defined in formula (I) and L is hydroxyby treatment with a halogenating agent such as phosphorus oxychloride.The reaction may be carried out in the presence of a base such as2-picoline at a temperature between 0° C. and 150° C.

Compounds of formula (IX) where R¹ is as defined in formula (I) and L ishydroxy may be prepared from compounds of formula (X) by treatment witha compound of formula R¹X where R¹ is as defined above and X is aleaving group such as bromide. The reaction may be carried out in asolvent such as aqueous DMF using a base such as potassium hydroxide atroom temperature.

Compounds of formula (VI) and (X) are commercially available.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (I) may involve, at an appropriate stage, theremoval of one or more protecting groups. The protection anddeprotection of functional groups is fully described in ‘ProtectiveGroups in Organic Chemistry’, edited by J. W. P. McOmie, Plenum Press(1973), and ‘Protective Groups in Organic Synthesis’, 2nd edition, T. W.Greene & P. G. M. Wuts, Wiley-Interscience (1991).

Novel intermediate compounds form a further aspect of the invention. Inparticular an intermediate of formula (IIA) is provided. Preferably L isbromo; R² is hydrogen; R³ is CH(CH₃)CH₂OH; and R¹is benzyl substitutedby two fluorine atoms.

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt or solvate thereof, preferably a basicaddition salt such as sodium, potassium, calcium, aluminium, lithium,magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine,ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or anacid addition salt such as a hydrochloride, hydrobromide, phosphate,acetate, fumarate, maleate, tartrate, citrate, oxalate,methanesulphonate or p-toluenesulphonate.

The compounds of formula (I) above may be converted to apharmaceutically acceptable in vivo hydrolysable ester thereof. An invivo hydrolysable ester of a compound of formula (I) that contains acarboxy or a hydroxy group is, for example a pharmaceutically acceptableester which is hydrolysed in the human or animal body to produce theparent acid or alcohol. Such s esters can be identified byadministering, for example, intravenously to a test animal, the compoundunder test and subsequently examining the test animal's body fluid.

Suitable pharmaceutically acceptable esters for carboxy include C₁-C₆alkoxymethyl esters for example methoxymethyl, C₁-C₆ alkanoyloxymethylesters for example pivaloyloxymethyl, phthalidyl esters, C₃-C₈cycloalkoxycarbonyloxyC₁-C₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl andmay be formed at any carboxy group in the compounds of this invention.

Suitable pharmaceutically-acceptable esters for hydroxy includeinorganic esters such as phosphate esters (including phosphoramidiccyclic esters) and α-acyloxyalkyl ethers and related compounds which asa result of the in-vivo hydrolysis of the ester breakdown to give theparent hydroxy group/s. Examples of α-acyloxyalkyl ethers includeacetoxymethoxy and 2,2dimethylpropionyloxymethoxy. A selection ofin-vivo hydrolysable ester forming groups for hydroxy include C₁-C₁₀alkanoyl, for example formyl, acetyl; benzoyl; phenylacetyl; substitutedbenzoyl and phenylacetyl, C₁-C₁₀ alkoxycarbonyl (to give alkyl carbonateesters), for example ethoxycarbonyl; di-(C₁-C₄)alkylcarbamoyl andN-(di-(C₁-C₄)alkylaminoethyl)-N-(C₁-C₄)alkylcarbamoyl (to givecarbamates); di-(C₁-C₄)alkylaminoacetyl and carboxyacetyl. Examples ofring substituents on phenylacetyl and benzoyl include aminomethyl,(C₁-C₄)alkylaminomethyl and di-((C₁-C₄)alkyl)aminomethyl, and morpholinoor piperazino linked from a ring nitrogen atom via a methylene linkinggroup to the 3- or 4-position of the benzoyl ring. Other interestingin-vivo hydrolysable esters include, for example,R^(A)C(O)O(C₁-C₆)alkyl-CO—, wherein R^(A) is for example,benzyloxy-(C₁-C₄)alkyl, or phenyl). Suitable substituents on a phenylgroup in such esters include, for example,4-(C₁-C₄)piperazio(C₁-C₄)alkyl, piperazino-(C₁-C₄)alkyl andmorpholino-(C₁-C₄)alkyl.

The compounds of formula (I) have activity as pharmaceuticals, inparticular as modulators of chemokine receptor (especially CXCR2)activity, and may be used in the treatment (therapeutic or prophylactic)of conditions/diseases in human and non-human animals which areexacerbated or caused by excessive or unregulated production ofchemokines. Examples of such conditions/diseases include:

-   -   (1) (the respiratory tract) obstructive airways diseases        including chronic obstructive pulmonary disease (COPD); asthma,        such as bronchial, allergic, intrinsic, extrinsic and dust        asthma, particularly chronic or inveterate asthma (e.g. late        asthma and airways hyper-responsiveness); bronchitis; acute,        allergic, atrophic rhinitis and chronic rhinitis including        rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta,        rhinitis sicca and rhinitis medicamentosa; membranous rhinitis        including croupous, fibrinous and pseudomembranous rhinitis and        scrofoulous rhinitis; seasonal rhinitis including rhinitis        nervosa (hay fever) and vasomotor rhinitis; sarcoidosis,        farmer's lung and related diseases, fibroid lung and idiopathic        interstitial pneumonia;    -   (2) (bone and joints) rheumatoid arthritis, seronegative        spondyloarthropathies (including ankylosing spondylitis,        psoriatic arthritis and Reiter's disease), Behchet's disease,        Sjogren's syndrome and systemic sclerosis;    -   (3) (skin) psoriasis, atopical dermatitis, contact dermatitis        and other eczematous dermitides, seborrhoetic dermatitis, Lichen        planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa,        urticaria, angiodermas, vasculitides, erythemas, cutaneous        eosinophilias, uveitis, Alopecia areata and vernal        conjunctivitis;    -   (4) (gastrointestinal tract) Coeliac disease, proctitis,        eosinopilic gastro-enteritis, mastocytosis, Crohn's disease,        ulcerative colitis, food-related allergies which have effects        remote from the gut, e.g., migraine, rhinitis and eczema;    -   (5) (central and peripheral nervous system) Neurodegenerative        diseases and dementia disorders, e.g. Alzheimer's disease,        amyotrophic lateral sclerosis and other motor neuron diseases,        Creutzfeldt-Jacob's disease and other prion diseases, HIV        encephalopathy (AIDS dementia complex), Huntington's disease,        frontotemporal dementia, Lewy body dementia and vascular        dementia; polyneuropathies, e.g. Guillain-Barré syndrome,        chronic inflammatory demyelinating polyradiculoneuropathy,        multifocal motor neuropathy, plexopathies; CNS demyelination,        e.g. multiple sclerosis, acute disseminated/haemorrhagic        encephalomyelitis, and subacute sclerosing panencephalitis;        neuromuscular disorders, e.g. myasthenia gravis and        Lambert-Eaton syndrome; spinal diorders, e.g. tropical spastic        paraparesis, and stiff-man syndrome: paraneoplastic syndromes,        e.g. cerebellar degeneration and encephalomyelitis; CNS trauma;        migraine; and stroke;    -   (6) (other tissues and systemic disease) atherosclerosis,        Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus,        systemic lupus, erythematosus, Hashimoto's thyroiditis, type I        diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE        syndrome, lepromatous leprosy, and idiopathic thrombocytopenia        pupura; post-operative adhesions, and sepsis;    -   (7) (allograft rejection) acute and chronic following, for        example, transplantation of kidney, heart, liver, lung, bone        marrow, skin and cornea; and chronic graft versus host disease;    -   (8) Cancers, especially non-small cell lung cancer (NSCLC),        malignant melanoma, prostate cancer and squamous sarcoma, and        tumour metastasis, non melanoma skin cancer and chemoprevention        of metastases;    -   (9) Diseases in which angiogenesis is associated with raised        CXCR2 chemokine levels (e.g. NSCLC, diabetic retinopathy);    -   (10) Cystic fibrosis;    -   (11) Burn wounds & chronic skin ulcers;    -   (12) Reproductive Diseases (e.g. Disorders of ovulation,        menstruation and implantation, Pre-term labour, Endometriosis);    -   (13) Re-perfusion injury in the heart, brain, peripheral limbs        and other organs, inhibition of atherosclerosis.

Thus, the present invention provides a compound of formula (I), or apharmaceutically-acceptable salt or solvate thereof, as hereinbeforedefined for use in therapy.

The present invention also provides a pharmaceutically acceptable invivo hydrolysable ester of a compound of formula (I), as hereinbeforedefined for use in therapy.

Preferably the compounds of the invention are used to treat diseases inwhich the chemokine receptor belongs to the CXC chemokine receptorsubfamily, more preferably the target chemokine receptor is the CXCR2receptor.

Particular conditions which can be treated with the compounds of theinvention are psorisis, rheumatoid arthritis, diseases in whichangiogenesis is associated with raised CXCR2 chemokine levels, andrespiratory disease such as COPD. It is preferred that the compounds ofthe invention are used to treat rheumatoid arthritis. The compounds ofthe invention may also be used to treat COPD.

As a further aspect of the present invention, certain compounds offormula (I) may have utility as antagonists of the CX3CR1 receptor. Suchcompounds are expected to be particularly useful in the treatment ofdisorders within the central and peripheral nervous system and otherconditions characterized by an activation of microglia and/orinfiltration of leukocytes (e.g. stroke/ischemia and head trauma).

In another aspect, the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, as hereinbefore defined as a medicament.

In another aspect, the present invention provides the use of apharmaceutically acceptable in vivo hydrolysable ester of a compound offormula (I), as hereinbefore defined as a medicament.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in therapy.

The present invention also provides the use of a pharmaceuticallyacceptable in vivo hydrolysable ester of a compound of formula (I), ashereinbefore defined in the manufacture of a medicament for use intherapy.

In a still further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for the treatment of human diseases or conditions in whichmodulation of chemokine receptor activity is beneficial.

The present invention also provides the use of a pharmaceuticallyacceptable in vivo hydrolysable ester of a compound of formula (I), ashereinbefore defined in the manufacture of a medicament for thetreatment of human diseases or conditions in which modulation ofchemokine receptor activity is beneficial.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention still further provides a method of treating a chemokinemediated disease wherein the chemokine binds to a chemokine (especiallyCXCR2) receptor, which comprises administering to a patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined.

The invention also provides a method of treating a chemokine mediateddisease wherein the chemokine binds to a chemokine (especially CXCR2)receptor, which comprises administering to a patient a therapeuticallyeffective amount of a pharmaceutically acceptable in vivo hydrolysableester of a compound of formula (I), as hereinbefore defined.

The invention also provides a method of treating an inflammatorydisease, especially psoriasis, in a patient suffering from, or at riskof, said disease, which comprises administering to the patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined.

The invention further provides a method of treating an inflammatorydisease, especially psoriasis, in a patient suffering from, or at riskof, said disease, which comprises administering to the patient atherapeutically effective amount of a pharmaceutically acceptable invivo hydrolysable ester of a compound of formula (I), as hereinbeforedefined

The invention also provides a method of treating an inflammatorydisease, especially rheumatoid arthritis, COPD and psoriasis, in apatient suffering from, or at risk of, said disease, which comprisesadministering to the patient a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined.Preferably the method of treating rheumatoid arthritis is provided. Alsoprovided is a method of treating COPD.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

The compounds of formula (I) and pharmaceutically acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (per cent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The present invention further provides a pharmaceutical compositioncomprising a pharmaceutically acceptable in vivo hydrolysable ester of acompound of formula (I), as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined, with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing apharmaceutically acceptable in vivo hydrolysable ester of a compound offormula (I), as hereinbefore defined, with a pharmaceutically acceptableadjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe lung and/or airways or to the skin) in the form of solutions,suspensions, heptafluoroalkane aerosols and dry powder formulations; orsystemically, e.g. by oral administration in the form of tablets,capsules, syrups, powders or granules, or by parenteral administrationin the form of solutions or suspensions, or by subcutaneousadministration or by rectal administration in the form of suppositoriesor transdermally. Preferably the compounds of the invention areadministered orally.

The invention will now be further illustrated by reference to thefollowing examples. In the examples the Nuclear Magnetic Resonance (NMR)spectra were measured on a Varian Unity Inova 300 or 400 MHzspectrometer and the Mass Spectrometry (MS) spectra measured on aFinnigan Mat SSQ7000 or Micromass Platform spectrometer or Agilent MSDspectrometer. Where necessary, the reactions were performed under aninert atmosphere of either nitrogen or argon. Chromatography wasgenerally performed using Matrex Silica 60® (35-70 micron) or ProlaboSilica gel 60® (35-70 micron) suitable for flash silica gelchromatography. High pressure liquid chromatography purification wasperformed using a Waters Micromass LCZ with a Waters 600 pumpcontroller, Waters 2487 detector and Gilson FC024 fraction collector ora Waters Delta Prep 4000 or a Gilson Auto-Purification System. Theabbreviations m.p. and DMSO used in the examples stand for melting pointand dimethyl sulphoxide respectively.

EXAMPLES Example 12-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-hydroxyethyl)amino]4-[[(1R)-2hydroxy1-methylethyl]amino]-7(8H)-pteridinonea) 2-[[(2,3-Difluorophenyl)methyl]thio]-4,6-pyrimidinediamine

4,6-diamino-2-pyrimidinethiol (7.3 g) was dissolved in DMSO (100 ml) atroom temperature under an atmosphere of nitrogen. Potassiumtert-butoxide (1M in THF, 48.3 ml) was added followed by2,3-difluorobenzyl-bromide (10.0 g). The mixture was stirred for 2 hoursat room temperature. The reaction mixture was then partitioned betweenethyl acetate and ammonium chloride. The organic phase was washed withammonium chloride (3×) and brine, then dried over magnesium sulphate andevaporated to give the subtitled product as a white solid (12.2 g)

MS: ADCI (+ve) 269 (M+1)

b) 2-[[(2,3-Difluorophenyl)methyl]thio]-5-nitroso-4,6-pyrimidinediamine

The product of Example 1, step (a) (2.5 g) was dissolved in acetic acid(150 ml) and the solution cooled to 5° C. A solution of sodium nitrite(625 mg) in water (50 ml) was added dropwise resulting in a dark bluecolouration. The reaction was stirred at room temperature for 30 minutesduring which time a pink solid precipitated from solution. This wasisolated by filtration and washed with water, then dried at 50° C. togive the subtitled product as a blue is solid (4.14 g)

MS: ADCI (+ve) 298 (M+1) ¹H NMR: δ (DMSO) 4.44 (s,2H), 7.13-7.54 (m,3H),8.13 (s,1H), 8.51 (s,1H), 9.10 (s,1H), 10.18 (s,1H).

c) 4-amino-2-[[(2,3-difluorophenyl)methyl]thio]-7(8H)pteridinone

To a solution of triethyl phosphonoacetate (15.0 g) in tetrahydrofuran(60 ml) cooled in an ice bath was added butyllithium (2.5M in hexanes,25.6 ml) at a rate such that the internal temperature was maintainedbelow 30° C. To this mixture was then added a solution of the product ofExample 1, step (b) (10.0 g) in N,N-dimethylformamide (60 ml). Thereaction mixture was heated at reflux for 1 hour, then cooled to roomtemperature and quenched with acetic acid (6 ml). The solid thusprecipitated was isolated by filtration, washed with water, ethanol anddiethyl ether, and dried over P₂O₅ at 50° C. to give the sub-titledproduct as a pale green solid (9.3 g).

MS: ADCI (+ve) 322 (M+1) ¹H NMR: δ (DMSO) 4.18 (s,2H), 7.11-7.58 (m,3H),7.84 (s,1H), 12.69 (bs,1H)

d) 4-bromo-2-[[(2,3-difluorophenyl)methyl]thio]-7(8H)-pteridinone

The product of Example 1, step (c) (0.5 g) was suspended in DMSO (10 ml)and bromoform (10 ml) and the mixture was heated to 125° C.Isoamylnitrite (2 ml) was added and the mixture was stirred at 125° C.for 5 minutes before being cooled in an ice bath. Solvent was removed byevaporation under high vacuum and the residue suspended indichloromethane (100 ml). This suspension was washed with saturatedaqueous ammonium chloride (50 ml) and then filtered through a plug ofcelite. The filtrate was evaporated and purified by columnchromatography, eluting with 10% ethyl acetate in dichloromethane togive the subtitled compound as a white solid (0.22 g).

MS: ADCI (+ve) 386 (M+1) ¹H NMR: δ (DMSO) 4.47 (s,2H), 7.13-7.55 (m,3H),8.14 (s,1H), 13.33 (bs,1H)

e)2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

The product of Example 1, step (d) (8.7 g) was dissolved inN-methylpyrrolidinone (40 ml) and Hunigs base (7.9 ml) was addedfollowed by D-alaninol (2.7 ml). The mixture was stirred at 100° C. for15 mins. The cooled solution was poured onto water, (1 l), and acidifiedwith dilute hydrochloric acid. The solid which separated was collected,washed with water and air dried. Crystallisation from acetonitrileafforded the title compound as a pale yellow solid (7.4 g).

m.p. 215-217° C. MS: APCI (+ve) 380 (M+H, 100%) ¹H NMR: δ (DMSO) 1.14(d, 3H), 3.48 (m, 2H, 4.31 (m, 1M), 4.45 (dd, 2H) 4.82 (t, 1H) 7.15 (m,1H), 7.33 (m, 1H), 7.47 (t, 1H), 7.76 (d, 1H), 7.83 (d,1H), 12.70 (s,1H).

(f)6-bromo2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)pteridinone

The product of Example 1, step (e) (5.0 g) was suspended in acetonitrile(200 ml) and bromine (1.2 ml) added. The reaction was stirred at roomtemperature for 2 hours, then evaporated to dryness. The crude productwas purified by column chromatography on silica gel, eluting with 2%methanol in dichloromethane to give the subtitled compound as a paleyellow solid (1.7 g).

MS: APCI (+ve) 458/460 (M+H, 100%) ¹H NMR: δ (DMSO) 7.76 (d, 1H), 7.47(m, 1H), 7.33 (m, 1H, 7.16 (m, 1H), 4.85 (t, 1H), 4.45 (q, 1H), 4.34 (m,1H), 3.54 (m, 1H), 3.45 (m, 1H), 1.15 (d, 3H).

(g)2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-hydroxyethyl)amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)pteridinone

The product of Example 1, step (f) (50 mg), ethanolamine (13 mg) andN,N-diisopropylethylamine (38 ul) were dissolved inN-methylpyrrolidinone (2 ml) and heated to 100° C. for 2 hours. Thecooled reaction mixture was diluted with ethyl acetate and washed 5×with saturated aqueous ammonium chloride. The organic phase was driedover magnesium sulphate, filtered and evaporated. The crude product waspurified by column chromatography on silica gel, eluting with 10%methanol in dichloromethane, followed by trituation with methanol togive the titled compound as a white solid (10 mg).

m.p. 197-199° C. MS: APCI (+ve) 439 (M+H, 100%) ¹H NMR: δ (DMSO) 12.45(br s, 1H), 7.45 (m, 1H), 7.29 (m, 2H), 7.14 (m, 1H), 6.66 (d, 1H), 4.87(t, 1H), 4.77 (t, 1H), 4.40 (s, 2H), 4.22 (m, 1H), 3.59 (m, 2H), 3.49(m, 4H), 1.16 (d, 3H).

Example 22-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(phenylmethyl)amino]-7(8H)-pteridinone

The product of Example 1, step (f) (50 mg), benzylamine (35 mg) andN,N-diisopropylethylamine (38 ul) were dissolved inN-methylpyrrolidinone (2 ml) and heated to 100° C. for 2 hours. Thecooled reaction mixture was diluted with ethyl acetate and washed 5×with saturated aqueous ammonium chloride. The organic phase was driedover magnesium sulphate, filtered and evaporated. The crude product waspurified by column chromatography on silica gel, eluting with 2%methanol in dichloromethane to give the titled compound as a pale yellowsolid (24 mg).

m.p. 80-100° C. MS: APCI (+ve) 485 (M+H, 100%) ¹H NMR: δ (DMSO) 9.10 (brs, 1H), 7.35 (m, 6H), 7.02 (m, 2H), 6.57 (br t, 1H), 6.07 (br, d, 1H),4.62 (m, 2H), 4.38 (s, 2H), 4.33 (m, 1H), 3.76 (m, 1H), 3.64 (m, 1H),2.62 (m, 1H), 1.28 (d, 3H).

Example 32-[[(2,3-Difluorophenyl)methyl]thio-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6,7-pteridinedione(a) 6-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinol,

To a stirred suspension of 4-amino-6-hydroxy-2-mercaptopyrimidinemonohydrate (50 g) in DMP (600 ml) was added potassium hydroxide (20.2g), water (100 ml) and 2,3-difluorobenzyl bromide (64.2 g). The reactionwas stirred at room temperature for 30 min. The mixture was poured intowater (4 l) and the resulting precipitate isolated by filtration,washing with isopropanol, to afford the subtitled compound as a whitesolid (73.7 g).

m.p. 218-221° C. MS: APCI+ve 270 (M+H, 100%) ¹H NMR: δ (DMSO) 7.37 (1H,m), 7.35 (1H, m), 7.16 (1H, m), 6.57 (3H, m), 4.99 (1H, br s), 4.39 (2H,s).

(b) 6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinamine

The product of Example 3, step (a) (73 g) was added to a solution of2-picoline (40 ml) in POCl₃ (300 ml) and the mixture refluxed for 24 hr.The reaction mixture was concentrated in vacuo to half its originalvolume and poured onto ice and then neutralized with ammonia, forming abrown solid. This mixture was refluxed for 1 hr, and the precipitateisolated by filtration, washing with water. The crude product waspurified by silica gel chromatography, eluting with dichloromethane toafford the subtitled compound as a white solid (31.7 g).

MS: APCI (+ve) 288/290 (M+H, 100%) ¹H NMR: δ (DMSO) 7.33 (5H, m), 7.12(1H, m), 4.36 (2H, s).

(c)(2R)-2-[[6-amino-2-[[(2,3difluorophenyl)methyl]thio]-4-pyrimidinyl]amino]-1-propanol

A solution of the product from Example 3, step (b) (22 g),N,N-diisopropylethylamine (110 ml) and D-alaninol (23 g) in NMP (150 ml)was heated at 160° C. for 48 h. The reaction mixture was allowed to coolto room temperature and poured into aqueous ammonium chloride (1.2 l).The resultant white precipitate was purified by silica gelchromatography, eluting first with 3:2 DCM:ethyl acetate and then 3:1DCM:methanol, giving the subtitled product as a pink solid (22.6 g).

MS: APCI (+ve) 327 (M+H, 100%) ¹H NMR: δ (DMSO) 7.38 (1H, m), 7.29 (1H,m), 7.10 (1H, m), 6.40 (1H, d), 6.13 (2H, bs), 5.15 (1H, s), 4.66 (1H,t), 4.31 (2H, t), 4.02 (1H, bs), 3.39 (1H, m), 3.25 (1H, m), 1.05 (3H,d).

(d)(R)-2-[[6-amino-2-[[(2,3-difluorophenyl)methyl]thio]-5-nitroso-4-pyrimidinyl]amino]-1-propanol

To a stirred solution of the product from Example 3, step (c) (22 g) inacetic acid (300 ml) at room temperature was added a solution of sodiumnitrite (4.8 g) in water (30 ml). The reaction was stirred at 0° C. for30 min, and the resultant purple precipitate isolated by filtration,washing with water, to give the subtitled compound as a dark blue solid(37 g, not completely dry).

MS: APCI (+ve) 356 (M+H, 100%)

(e)(2R)-2-[[5,6-diamino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]amino]-1-propanol

To a solution of acetic acid (10 ml) in boiling ethanol (300 ml) wasadded zinc dust (15 g) and the product of Example 3, step (d) (10 g).The reaction was heated at reflux for 10 mins, cooled, filtered throughcelite and the filtrate evaporated. The crude product was trituratedwith water, filtered and dried in vacuo to to give the subtitled productas a cream solid (9.3 g).

MS: APCI (+ve) 342 (M+H, 100%) ¹H NMR: δ (DMSO) 7.34 (1H, m), 7.27 (1H,m), 7.12 (1H, m), 5.72 (2H, b s), 5.58 (1H, d), 4.65 (1H, t), 4.30 (2H,d), 4.04 (1H, m), 3.54 (2H, bs), 3.44 (1H, m), 3.29 (1H, m), 1.09 (3H,d).

(f)2-[[(2,3-Difluorophenyl)methyl]thio-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6,7-pteridinedione

The product of Example 3, step (e) (0.30 g) and diethyloxalate wereheated at 160° C. for 30 mins. The mixture was concentrated in vacuo.Purification by flash chromatography over silica usingdichloromethane/methanol (9:1) as eluant afforded the title compound(0.045 g).

m.p. 243-246° C. MS: APCI 396 (M+H, 100%) ¹H NMR: δ (DMSO) 1.12 (d, 3H),3.43 (m, 2H), 4.14 (m, 1H), 4.38 (q, 2H), 6.79 (d, 1H), 7.13 (m, 1H),7.30 (m, 1H), 7.45 (t, 1H).

Example 46-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

To a solution of the product from Example 3, step (e) (190 mg) inethanol (30 ml) was added iminomethoxy-acetic acid, methyl esterhydrochloride (85 mg) (J. Chem. Soc., Perkin 1, 1999, 1783-93) followedby N,N-diisopropylethylamine (70 ul) and the mixture heated under refluxis for 24 hours. The mixture was evaporated to dryness and purified bysilica chromatography (ethyl acetate) to give the title compound (55mg).

MS APCI+ve 395 (M+H, 100%) ¹H NMR: δ (DMSO) 12.45 (bs, 1H), 7.45 (t,1H), 7.31 (m, 1H), 7.27 (m, 1H), 7.06 (bst, 2H), 6.49 (d,1H), 4.91 (t,1H), 4.36 (ab, 2H), 4.17 (m, 1H), 3.47 (t, 2H), 1.13 (d, 3H).

Example 52-[(2,3-Difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(1H-imidazol-1-yl)-7(8H)-pteridinone

The product of Example 1, step (f) (250 mg), imidazole (445 mg) andpotassium tert-butoxide (5.5 ml, 1M solution in THF) were dissolved inDMSO (10 ml) and the mixture heated to 100° C. for 1 hour. The cooledreaction mixture was diluted with ethyl acetate and washed 2× withsaturated aqueous ammonium chloride and 2× with water. The organic phasewas dried over magnesium sulphate, filtered and evaporated to give ayellow solid, which was recrystallised twice from acetonitrile/methanolto give the title compound (30 mg).

MS APCI+ve 446 (M+H, 100%) ¹H NMR: δ (DMSO) 13.19 (s, 1H), 8.95 (s, 1H),8.38 (s, 1H), 7.71 (d, 1H), 7.49 (m, 1H), 7.34 (m, 1H), 7.16 (m, 1H),7.11 (s,1H), 4.85 (t, 1H), 4.46 (ab, 2H), 4.30 (m, 1H), 3.50 (m, 2H),1.19 (d, 3H).

Example 62-[[2,3-Difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(1-methyl-1H-imidazol-2-yl)thio]-7(8H)-pteridinone

The product of Example 1, step (f) (250 mg),1-methyl-1H-imidazole-2-thiol (375 mg) and butyllithium (0.6 ml, 2.5Msolution in hexanes) were dissolved in N-methylpyrrolidinone (10 ml) andthe mixture heated to 100° C. for 2 hours. The cooled reaction mixturewas diluted with ethyl acetate and washed 4× with saturated aqueousammonium chloride. The organic phase was dried over magnesium sulphate,filtered and evaporated. The crude product was purified by silicachromatography (20:1 dichloromethane:methanol) to give the titlecompound (95 mg).

m.p. 216-217° C. MS APCI+ve 492 (M+H, 100%) ¹H NMR: δ (DMSO) 13.00 (s,1H), 7.52 (s, 1H), 7.42 (t, 1H), 7.30 (m, 1H), 7.13 (m, 2H), 5.97 (d,1H), 4.90 (br s, 1H), 4.42 (s, 2H), 4.05 (m, 1H), 3.59 (s, 3H), 3.38 (m,2H), 1.06 (d, 3H).

Example 72-[[2,3-Difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-methoxy-7(8H)-pteridinone

The product of Example 1, step (f) (250 mg) was dissolved in methanol(10 ml) and butyllithium (0.6 ml, 2.5M solution in hexanes) was added.The mixture was heated at reflux for 48 hours. The cooled reactionmixture was evaporated and purified by silica chromatography (20:1dichloromethane:methanol) followed by recrystallisation from methanol togive the title compound (15 mg).

MS APCI+ve 410 (M+H, 100%) ¹H NMR: δ (DMSO) 7.46 (t, 1H), 7.32 (q, 1H),7.13 (m, 1H), 6.96 (br d, 1H), 4.86 (t, 1H), 4.42 (ab, 2H), 4.28 (m,1H), 3.97 (s, 3H), 3.47 (m, 2H), 1.16 (d, 3H).

Examples 8 to 36

Examples 8 to 36 were prepared by the method of Example 1 step (g) byreaction of the product of Example 1, step (f) with the appropriateamine or thiol. The product purified by either (a) column chromatographyon silica gel, eluting with 10% methanol in dichloromethane, followed bytrituration with methanol or (b) reverse phase chromatography using aWaters Xterra column with acetonitrile and 0.2% 0.880 NH₄OH solution asbuffer to give the products as a solid as shown in table 1. TABLE 1Example Number Compound Name MS: APCI (+ve) 82-[[2,3-difluorophenyl)metbyl]thio]-4-[[(1R)-2-hydroxy- 4861-methylethyl]amino]-6-[(3-pyridinylmethyl)amino]- (M + H,7(8H)-pteridinone 100%) 92-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 4891-methylethyl]amino]-6-[[(5-methyl-2- (M + H,furanyl)methyl]amino]-7(8H)-pteridinone 100%) 102-[[2,3-difluorophenyl)methyl]thio]-6-[(3R,5S)-3,5- 492dimethyl-1-piperazinyl]-4-[[(1R)-2-hydroxy-1- (M + H,methylethyl]amino]-7(8H)-pteridinone 100%) 112-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 4461-methylethyl]amino]-6-[methyl[(3-methyl-5- (M + H,isoxazolyl)methyl]amino]-7(8H)-pteridinone 100%) 122-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 5161-methylethyl]amino]-6-[[2-(2- (M + H,pyrimidinylamino)ethyl]amino]-7(8H)-pteridinone 100%) 132-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 4651-methylethyl]amino]-6-(4-morpholinyl)-7(8H)-pteridinone (M + H, 100%)14 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 5081-methylethyl]amino]-6-[[2-(4-morpholinyl)ethyl]amino]- (M + H,7(8H)-pteridinone 100%) 152-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 4531-methylethyl]amino]-6-[(2-methoxyethyl)amino]-7(8H)- (M + H,pteridinone 100%) 16 2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2- 475furanylmethyl)amino]-4-[[(1R)-2-hydroxy-1- (M + H,methylethyl]amino]-7(8H)-pteridinone 100%) 176-(1-azetidinyl)-2-[[(2,3-difluorophenyl)methyl]thio]-4- 435[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone (M + H, 100%) 182-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 5011-methylethyl]amino]-6-[[(5- (M + H,methylpyrazinyl)methyl]amino]-7(8H)-pteridinone 100%) 192-[[(2,3-difluorophenyl)methyl]thio]-6-[[2-(2- 489furanyl)ethyl]amino]-4-[[(1R)-2-hydroxy-1- (M + H,methylethyl]amino]-7(8H)-pteridinone 100%) 202-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 5221-methylethyl]amino]-6-[[3-(4-morpholinyl)propyl]amino]- (M + H,7(8H)-pteridinone 100%) 212-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 4901-methylethyl]amino]-6-[[(3-methyl-5- (M + H,isoxazolyl)methyl]amino]-7(8H)-pteridinone 100%) 222-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 4651-methylethyl]amino]-6-[(3S)-3-hydroxy-1-pyrrolidinyl]- (M + H,7(8H)-pteridinone 100%) 23 2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-492 furanylmethyl)thio]-4-[[(1R)-2-hydroxy-1- (M + H,methylethyl]amino]-7(8H)-pteridinone 100%) 242-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 4531-methylethyl]amino]-6-[(2-hydroxypropyl)amino]-7(8H)- (M + H,pteridinone 100%) 25 2-[[(2,3-difluorophenyl)methyl]thio]-6-[[2- 483(dimethylamino)ethyl]thio]-4-[[(1R)-2-hydroxy-1- (M + H,methylethyl]amino]-7(8H)-pteridinone 100%) 262-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 4531-methylethyl]amino]-6-[[(2S)-2-hydroxypropyl]amino]- (M + H,7(8H)-pteridinone 100%) 272-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 4531-methylethyl]amino]-6-[(3-hydroxypropyl)amino]-7(8H)- (M + H,pteridinone 100%) 28 2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2- 453hydroxyethyl)methylamino]-4-[[(1R)-2-hydroxy-1- (M + H,methylethyl]amino]-7(8H)-pteridinone 100%) 292-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 5091-methylethyl]amino]-6-[(5-hydroxy-4-methyl-4H-1,2,4- (M + H,triazol-3-yl)thio]-7(8H)-pteridinone 100%) 302-[[(2,3-difluorophenyl)methyl]thio]-6-[(4- 493hydroxycyclohexyl)amino]-4-[[(1R)-2-hydroxy-1- (M + H,methylethyl]amino]-7(8H)-pteridinone 100%) 312-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 4961-methylethyl]amino]-6-(1,3,4-thiadiazol-2-ylthio)-7(8H)- (M + H,pteridinone 100%) 32 2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(1S,4R)-4-477 hydroxy-2-cyclopenten-1-yl]amino]-4-[[(1R)-2-hydroxy-1- (M + H,methylethyl]amino]-7(8H)-pteridinone 100%) 332-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy- 4651-methylethyl]amino]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]- (M + H,7(8H)-pteridinone 100%) 342-[[(2,3-difluorophenyl)methyl]thio]-6-(3-hydroxy-3- 465methyl-1-azetidinyl)-4-[[(1R)-2-hydroxy-1- (M + H,methylethyl]amino]-7(8H)-pteridinone 100%) 356-[(3S)-3-amino-1-pyrrolidinyl]-2-[[(2,3- 464difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1- (M + H,methylethyl]amino]-7(8H)-pteridinone 100%) 366-[(2-aminoethyl)thio]-2-[[(2,3- 453difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1- (M + H,methylethyl]amino]-7(8H)-pteridinone 100%)Pharmacological DataLigand Binding Assay

[¹²⁵I]IL-8(human, recombinant) was purchased from Amersham, U.K. with aspecific activity of 2,000 Ci/mmol. All other chemicals were ofanalytical grade. High levels of hrCXCR2 were expressed in HEK 293 cells(human embryo kidney 293 cells ECACC No. 85120602) (Lee et al. (1992) J.Biol. Chem. 267 pp16283-16291). hrCXCR2 cDNA was amplified and clonedfrom human neutrophil mRNA. The DNA was cloned into PCRScript(Stratagene) and clones were identified using DNA. The coding sequencewas subcloned into the eukaryotic expression vector RcCMV (Invitrogen).Plasmid DNA was prepared using Quiagen Megaprep 2500 and transfectedinto HEK 293 cells using Lipofectamine reagent (Gibco BRL). Cells of thehighest expressing clone were harvested in phosphate-buffered salinecontaining 0.2% (w/v) ethylenediaminetetraacetic acid (EDTA) andcentrifuged (200 g, 5 min.). The cell pellet was resuspended in ice coldhomogenisation buffer [10 mM HEPES (pH 7.4), 1 mM dithiothreitol, 1 mMEDTA and a panel of protease inhibitors (1 mM phenyl methyl sulphonylfluoride, 2 μg/ml soybean trypsin inhibitor, 3 mM benzamidine, 0.5 μg/mlleupeptin and 100 μg/ml bacitracin)] and the cells left to swell for 10minutes. The cell preparation was disrupted using a hand held glassmortar/PTFE pestle homogeniser and cell membranes harvested bycentrifugation (45 minutes, 100,000 g, 4° C.). The membrane preparationwas stored at −70° C. in homogenisation buffer supplemented withTyrode's salt solution (137 mM NaCl, 2.7 mM KCl, 0.4 mM NaH₂PO₄), 0.1%(w/v) gelatin and 10% (v/v) glycerol.

All assays were performed in a 96-well MultiScreen 0.45 μm filtrationplates (Mllipore, U.K.). Each assay contained ˜50 pM [125I]IL-8 andmembranes (equivalent to ˜200,000 cells) in assay buffer [Tyrode's saltsolution supplemented with 10 mM HEPES (pH 7.4), 1.8 mM CaCl₂, 1 mMMgCl₂, 0.125 mg/ml bacitracin and 0.1% (w/v) gelatin]. In addition, acompound of formula (I) according to the Examples was predissolved inDMSO and added to reach a final concentration of 1% (v/v) DMSO. Theassay was initiated with the addition of membranes and after 1.5 hoursat room temperature the membranes were harvested by filtration using aMillipore MultiScreen vacuum manifold and washed twice with assay buffer(without bacitracin). The backing plate was removed from the MultiScreenplate assembly, the filters dried at room temperature, punched out andthen counted on a Cobra γ-counter.

The compounds of formula (I) according to the Examples were found tohave IC₅₀ values of less than (<) 10 μM.

Intracellular Calcium Mobilisation Assay

Human neutrophils were prepared from EDTA-treated peripheral blood, aspreviously described (Baly et al. (1997) Methods in Enzymology 287pp70-72), in storage buffer ∂Tyrode's salt solution (137 mM NaCl, 2.7 mMKCl, 0.4 mM NaH₂PO₄) supplemented with 5.7 mM glucose and 10 mM HEPES(pH 7.4)].

The chemokine GROα (human, recombinant) was purchased from R&D Systems(Abingdon, U.K.). All other chemicals were of analytical grade. Changesin intracellular free calcium were measured fluorometrically by loadingneutrophils with the calcium sensitive fluorescent dye, fluo-3, asdescribed previously (Merritt et al. (1990) Biochem. J. 269, pp513-519).Cells were loaded for 1 hour at 37° C. in loading buffer (storage bufferwith 0.1% (w/v) gelatin) containing 5 μM fluo-3 AM ester, washed withloading buffer and then resuspended in Tyrode's salt solutionsupplemented with 5.7 mM glucose, 0.1% (w/v) bovine serum albumin (BSA),1.8 mM CaCl₂ and 1 mM MgCl₂. The cells were pipetted into black walled,clear bottom, 96 well micro plates (Costar, Boston, U.S.A.) andcentrifuged (200 g, 5 minutes, room temperature).

A compound of formula (I) according to the Examples was pre-dissolved inDMSO and added to a final concentration of 0.1% (v/v) DMSO. Assays wereinitiated by the addition of an A₅₀concentration of GROα and thetransient increase in fluo-3 fluorescence (λ_(Ex)=490 nm and λ_(Em)520nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader,Molecular Devices, Sunnyvale, U.S.A.).

The compounds of formula (I) according to the Examples were tested andfound to be antagonists of the CXCR2 receptor in human neutrophils.

1. A compound of formula (I) or a pharmaceutically acceptable salt,solvate or in vivo hydrolysable ester thereof:

in which: R¹ represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenylor C₂-C₆ alkynyl group, each of which may be optionally substituted byone or more substituent groups independently selected from halogenatoms, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰,—SO₂NR⁵R⁶, —NR⁸SO₂R⁹, an aryl or heteroaryl group, which last two maythemselves be optionally substituted by one or more substituentsindependently selected from halogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶,—CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆alkyl or trifluoromethyl groups; R² and R³ each independently representa hydrogen atom, or a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl orC₂-C₆ alkynyl group, the latter four groups may be optionallysubstituted by one or more substituent groups independently selectedfrom: (a) halogen atoms, —OR⁴, —NR⁵R⁶—CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,—SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹; (b) a 3-8 membered ring optionallycontaining one or more atoms selected from O, S, NR⁸ and itselfoptionally substituted by C₁-C₃-alkyl or halogen; or (c) an aryl groupor heteroaryl group each of which may be optionally substituted by oneor more substituents independently selected from halogen atoms, cyano,nitro, —OR⁴, —NR⁵R⁶, -—CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆alkyl and trifluoromethyl groups; R⁴ represents hydrogen or a C₁-C₆alkyl group which may be optionally substituted by one or moresubstituent groups independently selected from halogen atoms, —OR¹¹,—NR⁵R⁶, or an aryl group or heteroaryl group either of which may beoptionally substituted by one or more substituents independentlyselected from halogen atoms, cyano, nitro, —OR¹¹, —NR⁵R⁶, —CONR⁵R⁶,—NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆ alkyl and trifluoromethyl groups;or R⁴ represents a halogen atom, —OR¹¹, —NR⁵R⁶, or an aryl group orheteroaryl group either of which may be optionally substituted by one ormore substituents independently selected from halogen atoms, cyano,nitro, —OR¹¹, —NR⁵R⁶, —CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆alkyl and trifluoromethyl groups; R⁵ and R⁶ independently represent ahydrogen atom or a C₁-C₆ alkyl or phenyl group or heteroaryl group thelatter three of which may be optionally substituted by one or moresubstituent groups independently selected from halogen atoms, phenyl,—OR¹⁴ and —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or R⁵and R⁶ together with the nitrogen atom to which they are attached form a4- to 7-membered saturated heterocyclic ring system optionallycontaining a further heteroatom selected from oxygen and nitrogen atoms,which ring system may be optionally substituted by one or moresubstituent groups independently selected from phenyl, —OR¹⁴, —COOR¹⁴,—NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶, —NR¹⁵SO₂R¹⁶ or C₁-C₆alkyl, itself optionally substituted by one or more substituentsindependently selected from halogen atoms and —NR¹⁵R¹⁶ and —OR¹⁷groups;R¹⁰ represents a C₁-C₆-alkyl or a phenyl group, either of whichmay be optionally substituted by one or more substituent groupsindependently selected from halogen atoms, phenyl, —OR¹⁷ and —NR¹⁵R¹⁶, Yis NR²⁰R²¹, OR⁴, SR⁴, a heteroaryl group or NR⁵R⁶ where R⁵ and R⁶together with the nitrogen atom to which they are attached form a 4- to7-membered saturated heterocyclic ring system optionally containing afurther heteroatom selected from oxygen and nitrogen atoms, which ringsystem may be optionally substituted by one or more substituent groupsindependently selected from phenyl, —OR¹⁴, —COOR¹⁴, —NR¹⁵R¹⁶,—CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁-C₆ alkyl, itselfoptionally substituted by one or more substituents independentlyselected from halogen atoms and -NR¹⁵R¹⁶ and —OR¹⁷ groups; each of R⁷,R⁸, R⁹, R¹¹, R¹⁵, R¹⁶and R¹⁷ independently represents a hydrogen atom ora C₁-C₆, alkyl, or a phenyl group; and R²⁰ and R²¹ are defined as for R²and R³.
 2. A compound according to claim 1, wherein R¹ represents anoptionally substituted benzyl group.
 3. A compound according to claim 2,wherein R¹ represents benzyl substituted by two halogen atoms.
 4. Acompound according to claim 1, wherein one of R² and R³ is hydrogen andthe other is C₃-C₄ alkyl substituted by one or more hydroxy groups.
 5. Acompound according to claim 1 wherein one of R² and R³ is hydrogen andthe other is CH(CH₃)CH₂OH, CH(Et)CH₂OH, C(CH₃)₂CH₂OH or CH(CH₂OH)₂.
 6. Acompound according to claim 1 wherein one of R² and R³ is hydrogen andthe other is CH(CH₃)CH₂OH.
 7. A compound according to claim 6 in theform of the (R) isomer.
 8. A compound according to claim 1 wherein Y is—NR²⁰R²¹, —OR⁴, —SR⁴, a heteroaryl group or —NR⁵R⁶ where R⁵ and R⁶together with the nitrogen atom to which they are attached form a 4- to7-membered saturated heterocyclic ring system optionally containing afurther heteroatom selected from oxygen and nitrogen atoms, which ringsystem may be optionally substituted by one or more substituent groupsindependently selected from —OH, —NH₂ or C₁-C₄ alkyl.
 9. A compoundaccording to claim 1 selected from:2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-hydroxyethyl)amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(phenylmethyl)amino]-7(8H)-pteridinone;2-[[(2,3-Difluorophenyl)methyl]thio-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6,7-pteridinedione;6-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;2-[[2,3-difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(1H-imidazol-1-yl)-7(8H)-pteridinone;2-[[2,3-difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(1-methyl-1H-imidazol-2-yl)thio]-7(8H)-pteridinone;2-[[2,3-difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-methoxy-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3-pyridinylmethyl)amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[(5-methyl-2-furanyl)methyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-6-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[methyl[(3-methyl-5-isoxazolyl)methyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[2-(2-pyrimidinylamino)ethyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(4-morpholinyl)-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[2-(4-morpholinyl)ethyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(2-methoxyethyl)amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-furanylmethyl)amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;6-(1-azetidinyl)-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[5-methylpyrazinyl)methyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-6-[[2-(2-furanyl)ethyl]amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[3-(4-morpholinyl)propyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[(3-methyl-5-isoxazolyl)methyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3S)-3-hydroxy-1-pyrrolidinyl]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-furanylmethyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(2-hydroxypropyl)amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-6-[[2-(dimethylamino)ethyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[(2S)-2-hydroxypropyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3-hydroxypropyl)amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-hydroxyethyl)methylamino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(5-hydroxy-4-methyl-4H-1,2,4-triazol-3-yl)thio]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-6-[(4-hydroxycyclohexyl)amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(1,3,4-thiadiazol-2-ylthio)-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(1S,4R)-4-hydroxy-2-cyclopenten-1-yl]amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-7(8H)-pteridinone;2-[[(2,3-difluorophenyl)methyl]thio]-6-(3-hydroxy-3-methyl-1-azetidinyl)-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;6-[(3S)-3-amino-1-pyrrolidinyl]-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone;and6-[(2-aminoethyl)thio]-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone.10. A process for the preparation of: (a) a compound of formula (I) asdefined in claim 1 where Y is NR²⁰R²¹ which comprises treatment of acompound of formula (IIA):

where R¹, R² and R³ are as defined in formula (I) or are protectedderivatives thereof and L is a leaving group such as bromo with an amineHNR²⁰R²¹, or (b) a compound of formula (I) as defined in claim 1 where Yis OR⁴ which comprises treatment of a compound of formula (IIA) whereR¹, R² and R³ are as defined in formula (I) or are protected derivativesthereof and L is a leaving group such as bromo with an alcohol R⁴OH, or(c) a compound of formula (I) as defined in claim 1 where Y is SR⁴ whichcomprises treatment of a compound of formula (IIA) where R¹, R² and R³are as defined in formula (I) or are protected derivatives thereof and Lis a leaving group such as bromo with a thiol R⁴SH, or (d) a compound offormula (I) where Y is NR⁵R⁶which comprises treatment of a compound offormula (IIA) where R¹, R² and R³ are as defined in formula (I) or areprotected derivatives thereof and L is a leaving group such as bromowith an amine H NR⁵R⁶, or (e) a compound of formula (I) where Y is aheteroaryl group which comprises treatment of a compound of formula(IIA) where R¹, R² and R³ are as defined in formula (I) or are protectedderivatives thereof and L is a leaving group such as bromo with aheteroarene, or (f) a compound of formula (I) as defined in claim 1where Y is OH which comprises treatment of a compound of formula (IIB):

where R¹, R² and R³ are as defined in formula (I) or are protectedderivatives thereof with diethyl oxalate, or (g) a compound of formula(I) as defined in claim 1 where Y is NH₂ which comprises treatment of acompound of formula (IIB) where R¹, R² and R³ are as defined in formula(I) or are protected derivatives thereof with iminomethoxy-acetic acid,methyl ester hydrochloride, and optionally thereafter process (a), (b),(c), (d) or (e) and in any order: removing any protecting groups forminga pharmaceutically acceptable salt, solvate or in vivo hydrolysableester.
 11. An intermediate compound of formula (IIA) as defined in claim10.
 12. A pharmaceutical composition comprising a compound of formula(I), or a pharmaceutically acceptable salt, solvate or in vivohydrolysable ester thereof, as claimed claim 1 in association with apharmaceutically acceptable adjuvant, diluent or carrier.
 13. A processfor the preparation of a pharmaceutical composition as claimed in claim12 which comprises mixing a compound of formula (I), or apharmaceutically acceptable salt, solvate or in vivo hydrolysable esterthereof, as claimed in claim 1 with a pharmaceutically acceptableadjuvant, diluent or carrier.
 14. A compound of formula (I), or apharmaceutically-acceptable salt, solvate or in vivo hydrolysable esterthereof, as claimed in claim 1 for use in therapy. 15.-16. (Cancelled).17. A method of treating a chemokine mediated disease wherein thechemokine binds to one or more chemokine receptors, which comprisesadministering to a patient a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as claimed in claim
 1. 18. Amethod according to claim 17 in which the chemokine receptor belongs tothe CXC chemokine receptor subfamily.
 19. A method according to claim 17in which the chemokine receptor is the CXCR2 receptor.
 20. A method oftreating an inflammatory disease in a patient suffering from, or at riskof, said disease, which comprises administering to the patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate or in vivo hydrolysable esterthereof, as claimed in claim
 1. 21. A method according to claim 20,wherein the disease is psoriasis, rheumatoid arthritis, a disease inwhich angiogenesis is associated with raised CXCR2 chemokine levels, orCOPD.
 22. A method according to claim 20, wherein the disease isrheumatoid arthritis.
 23. A method according to claim 20, wherein thedisease is COPD.